N([O-])=O.[Na+].[CH3:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][C:14]=2[F:20])=[CH:10][CH:9]=[C:8]([CH3:21])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.[BrH:34]>O.[Cu]Br>[Br:34][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[C:6]([CH3:5])=[N:7][C:8]([CH3:21])=[CH:9][CH:10]=2)=[C:14]([F:20])[CH:15]=1A solution of sodium nitrite (4.57 g, 66.3 mmol) in water (75 ml) was added dropwise (over 45 minutes) to a cooled (at 0° C.) solution of intermediate D15 (7.7 g, 33.2 mmol) in 48% aqueous HBr (75 ml). The reaction mixture was warmed to room temperature and further stirred for 15 minutes, after which it was cooled again to 0° C. and copper(I) bromide (7.31 g, 49.8 mmol) was added portionwise. The mixture was allowed to reach room temperature, stirred for 15 minutes and finally it was heated at 140° C. for 1.5 hours. The reaction mixture was cooled to room temperature and neutralized with an aqueous saturated solution of potassium carbonate. EtOAc was added, the organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-10% EtOAc/heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield D16 (8.75 g, 89%) as a pale brown oil.
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